Influenza

Influenza viruses A,B,C belong to

the family Orthomyxoviruses

26/11/2008 influenza 1
 Human influenza

26/11/2008 influenza 2
 Classical influenza
• Sudden onset of fever, chills, headache,
myalgia, anorexia
• Respiratory symptoms may be associated
with both URT + LRT infection, often with dry
cough
• Symptoms may vary with age, with adults
more likely to have systemic effects
• Long convalescent period of 1-2 weeks but
short incubation period of 1-4 days

26/11/2008 influenza 3
 Complications
• Viral pneumonia that may rapidly be
fatal
• Bacterial pneumonia due to 2o infection
later in illness
• Risk of such complications increases
with age
• Depending on strain: high case fatalities

26/11/2008 influenza 4
 Influenza viruses

26/11/2008 influenza 5
 Influenza A viral structure

26/11/2008 influenza 6
 Key features of influenza
viruses
• ssRNA within a helical capsid, itself surrounded by a
lipid envelope
• 3 proteins project through lipid: M2,
haemagglutinin(H) and neuraminidase(N)
• H contains 2 polypeptides, HA1 + HA2 concerned
with fusion with host cell – basis for effective
transmission (usually host specific)
• HA1 is very variable
• N is an enzyme cleaving sialic acid, has several
functions, most importantly virion release

26/11/2008 influenza 7
 Influenza A + human disease

• WHO describes each new isolate as

follows:
• A/host of origin/geographical origin/H+N
type e.g. A/avian/Hong Kong/H5N1
• 15 H antigens + 9 N antigens but only
certain ones are typically recorded in
man

26/11/2008 influenza 8
 Epidemiology

26/11/2008 influenza 9
 Any human population has
endemic influenza
• Caused by current influenza (A,B,C)
circulating
• Population will build up ‘herd immunity’
• Endemicity results from this balance
between new infections and immunity
• Balance will be upset by new strains
entering the population

26/11/2008 influenza 10
 Antigenic Drift and Shift: 1
• A can do both!
• B + C can only drift
• Both terms refer to the changes
observed in H + N profile of a virus
strain (reflect changes in coding RNA
sequences)
• Result from instability of viral RNA
during replication
26/11/2008 influenza 11
 Genome sequences of H5N1
avian influenza A virus in poultry
populations in Thailand.
Viseshakul et al. Virology 204;
328:169-176

26/11/2008 influenza 12
 Antigenic drift can lead to an
epidemic
• Antigenic drift is a gradual change that
occurs as the virus circulates through a
population
• results from small changes in RNA
sequence (and so subtle changes in H
or N
• Antibodies, either due to prior infection
or vaccination, cease to be protective

26/11/2008 influenza 13
 Epidemics: 1
• These are continuously occurring and
surveillance both nationally and by
WHO can help predict the most likely
new strain responsible
• Can do this by monitoring disease and
the RNA of isolates
• Such predictions enable protective
measures to be put in place

26/11/2008 influenza 14
 Antigenic shift can lead to a
pandemic
• Shift results from large changes in viral
genome, producing new combinations of H +
N
• Genetic reassortment between 2 parental
viruses has been demonstrated in the lab
• Coinfection might enable this to happen in a
human host
• Can see a very different virus appearing
without warning; no-one is immune!

26/11/2008 influenza 15
 Pandemics of the 20th century
(have occurred before 20thC but no reliable scientific records)

• 1918 Spanish flu’ • H1N1

• 1957 Asian flu’ • H2N2
• 1968 Hong Kong flu’ • H3N2
• 1977 red (Russian) • H1N1
flu’ • Different antigenic
strains except 1977
• Not clear why H1N1
reappeared!

26/11/2008 influenza 16
 I918 pandemic
(virus has been recently investigated)

• First influenza virus to be well

characterised
• Origin of this virus is unclear
• Genome has been sequenced but virus
was never isolated
• Geographical origin is UNKNOWN –
best called 1918 influenza, not Spanish!

26/11/2008 influenza 17
 I918 pandemic: 2
• Spread in 3 waves: Europe, Asia, N
America: ? 50 MILLION died during
1918-1919
• Although history suggests there was a
preceding epidemic of avian disease,
facts are not clear
• ORIGIN UNKNOWN!

26/11/2008 influenza 18
 I918 pandemic: 3
• High mortality – why?
• Biological basis could be that virus binding to
human host cells was highly effective in this
strain (not the case with an animal virus): this
would enable HUMAN TO HUMAN SPREAD
• High mortality in the v. young (also in young
adults)
• No antibiotics to treat secondary bacterial
infections

26/11/2008 influenza 19
 A Big worry!
• Could an apparently novel strain suddenly
appear (as in 1918) to cause a similar
pandemic?
• H5N1! Causative agent of avian influenza
• At first sight, H5N1 seems unlikely to repeat
1918
• Main reason: lack of evidence of ready
transmissibility from man to man

26/11/2008 influenza 20
 1997 Hong Kong
• Before this date, no evidence of an H5 virus
infecting man
• Novel virus appeared in China, spreading
from domestic ducks to chickens
• In chickens, became highly pathogenic to
other birds (chickens = site of reassortment
with other bird flu viruses)
• Then appeared in Hong Kong poultry markets

26/11/2008 influenza 21
 1997 Hong Kong: 2
• Threatened to be a new bird pandemic but
was controlled by mass slaughter of chickens
in Hong Kong(1.5 million in 3 days) – some
doing!
• Virus was H5N1 and DID jumped the
species barrier from chickens to man
directly
• 6 out of 18 infected persons died
• People only caught it from chickens since no
man to man transmission was demonstrated

26/11/2008 influenza 22
 Avian influenza

Influenza –like disease in birds

(human disease caused by avian
virus)

26/11/2008 influenza 23
 Avian influenza
• All birds, both domestic and wild, are thought
to be susceptible, showing a wide range of
symptoms
• All H and N variants have been demonstrated
• ‘Highly pathogenic avian influenza’ is caused
by subtypes H5 and H7
• Key role of wildfowl as natural and migratory
reservoirs
• Commercial production of chickens, turkeys
and ducks are an important factor now

26/11/2008 influenza 24
 Recent history: some examples

• 1983-84 in US • 1999-2001 Italy

• H5N2 caused a • H7N1 caused a
major epidemic in similar epidemic
poultry • 13 million birds
• 90% mortality slaughtered
• Control involve • As with US, caused
slaughter of 17 by low pathogenicity
million birds subtype mutating

26/11/2008 influenza 25
 H5N1: a particular concern
• Known to mutate rapidly (drift)
• Known to reassort frequently (shift)
• Can cause severe human and avian
disease
• Excreted for long periods by birds
• Current epidemic in Far East in birds –
since 2003, >120 million birds have
been culled (by early 2006)
26/11/2008 influenza 26
 General trend
• First seen in poultry flocks
• Often spread in commercial enterprises
• Then see a few cases in humans who
have contact with the poultry
• Working with birds or at markets

26/11/2008 influenza 27
 In the UK: H5N1
• Bernard Matthews turkeys in Suffolk in
early 2007
• Association with Hungary, virus
probably brought in infected meat
• Outbreak contained by culling 100,000
birds
• No prosecutions; compensation!

26/11/2008 influenza 28
 H5N1: a particular concern : 2

• If the avian strain infects a cell already

containing a human strain, it is possible
that a new recombinant virus will
emerge
• Might have properties of both: rapid
transmission in birds and man

26/11/2008 influenza 29
 Human disease: 2008
• Confirmed human cases have been
reported in 20 countries
• Originally just in the Far East but now
in Middle East, Turkey and Africa
• Most cases seen in Far East, especially
Vietnam and Indonesia
www.who.int/csr/disease/avian_influenza

26/11/2008 influenza 30
 WHO: confirmed human cases
by early September 2008
• Indonesia* 136 (94) • Egypt* 43 (19)
• China 30 (17) • Iraq 3 (2)
• Thailand 25 (17) • Turkey 12 (4)
• Vietnam 101 (47 • Nigeria 1 (1)
• THESE ARE VERY • * indicates most
HIGH MORTALITY new cases in
RATES!
2007

26/11/2008 influenza 31
 Current trends (WHO)
• 50% cases have been < 20 years old
• 90% have been < 40 years old
• Mortality rate is highest in oldest patients
• Overall fatalities:
• 2004: 69%
• 2005: 43%
• 2006: 68%
• 2007: 68%
26/11/2008 influenza 32
 H5N1 in man: why in SE Asia?

• H5N1 maybe naturally more widespread in

bird populations in this part of the world to
start with
• Diseased birds can shed virus for long
periods, which survives easily in tissues and
faeces in water at low temperatures
• Traditional lifestyle also predisposes to
mixing of people and birds in this area,
increasing chances of recombinant virus
production
26/11/2008 influenza 33
 Survival characteristics of H5N1:

–survives for up to 4 days at 22oC

–survives more than 30 days at
0oC
–survives in frozen material
indefinitely
–Think about dead chickens
before we eat them!
26/11/2008 influenza 34
 Defence strategies

Can we stop a new pandemic?

26/11/2008 influenza 35
 Pandemic preparedness
• November 2005: US published its plans:
www.hhs.gov/pandemicflu/plan/
• 2 possible strategies:
• Vaccination
• Use of antiviral drugs
• COST!

26/11/2008 influenza 36
 Vaccines
• Constant need for maintaining stocks to
protect most vulnerable against
prevailing strain
• Constant surveillance to predict need
for production + introduction of new
vaccine against new ‘epidemic’ strain
• Now have problem of vaccine against a
possible pandemic strain

26/11/2008 influenza 37
 ‘Pandemic vaccines’
• 2 types: for birds and for man
• Human vaccines are being planned,
produced and trialled
• Usually aimed at neutralising the HA
antigen
• Inactivated H5N1
• Inactivated H9N2 (shared antigenicity)
• Also a UK H5N1 vaccine
26/11/2008 influenza 38
 ? Universal flu jab
• December 2007/January 2008
• Claims by company, Acambis, that a
single vaccine can protect against ALL
strains on influenza A
• Targets M2 protein

26/11/2008 influenza 39
 Avian vaccines
• Only inactivated ones can be legally
used
• Activated ones exist and are known to
be used illegally
• Risk of using activated forms –
reassortment to produce a novel and
highly pathogenic virus in vaccinated
birds

26/11/2008 influenza 40
 Antiviral drugs
• Prophylaxis and treatment
• 2 types available: M2 protein inhibitors
and neuraminidase (N) inhibitors
• M2 protein inhibitors are cheaper and
limited for use against influenza e.g.
amantidine + rimantidine
• Can be used prophylactically

26/11/2008 influenza 41
 Antiviral drugs: 2
• 2 NAIs are zanamivir + oseltamivir* can
also be used for prophylaxis
• With treatment, it is thought that NAIs
may be better since there is less
likelihood of drug resistance appearing
• Stockpiling is inevitable!
• * = WHO drug of choice for treatment

26/11/2008 influenza 42
 Oseltamivir (Tamiflu)
• Roche
• Oral dose, twice a a day for 5 days
• Blocking neuraminidase activity
prevents release of new viruses
• Chemical synthesis is quite complex –
from shikimic acid – only obtainable in
large quantities from star anise, a
Chinese cooking spice
26/11/2008 influenza 43
 Oseltamivir resistance!
• NOT GOOD NEWS!
• Confined to A (H1N1)
• Increased numbers of influenza patients
with this was reported in Norway in
January 2008; previously in 2006/7 –
none
• Now being found in UK – 12 in
November 2008 – in W. England
26/11/2008 influenza 44